hallmarks of cancer

Question 1

10 hallmarks of cancer

Answer 1

1. growth signal autonomy
2. evasion of growth inhibitory signals
3. evasion of apoptosis
4. unlimited replicative potention
5. angiogenesis
6. infiltration & metastasis
7. avoiding immune destruction
8. reprogramming energy metabolism
9. genome instability
10. tumour promoting inflammation

Question 2

5 ways normal cells control cell division

Answer 2

1. binding of growth factor to specific receptor
2. transient & limited activation of growth factor receptor
3. cascade of biochemical events with eventual signal transduction to nucleus
4. induction & activation of nuclear regulatory factors that initiate DNA transcription
5. expression of genes involved in cell growth & cell signalling pathways

Question 3

example of increase in growth factor production

Answer 3

overexpression of PDGF (platelet derived growth factor)

Question 4

how can growth factor receptors change (2)

Answer 4

1. amplification (increase number of receptors)
2. change in structure of growth factor receptors to become constitutively active

Question 5

example of changes that amplifies normal receptors and hence signal pathways (2)

Answer 5

EGFR:
- occurs in 80% of colorectal cancers
- overexpression causes increase ligand binding that activates MAPK pathway

HER2:
- occurs in 33% of breast cancers
- leads to ligand independant activation

Question 6

examples of point mutations/deletions that amplify normal receptors and hence signal pathways (3)

Answer 6

EGFR
- occurs in 60% of lung adenocarcinoma
- exon 19 deletions or L858 point mutations make RTK constitutively active

BRAF (RAS) mutations
- occurs in 100% of hairy cell leukemia
- mutation to oncogene leads to constitutive activation of signal transduction proteins

P13K mutations
- leads to constitutive activation of signal transduction proteins

Question 7

example of gene arrangement/translocation that leads to amplification of signal pathways

Answer 7

ALK
- gene rearrangement to EML4-ALK fusion gene stimulates downstream pathways
- occurs in 5% of lung adenocarcinoma

Question 8

example of mutation that activates transcription factors

Answer 8

(upregulation of) MYC
- occurs in burkitt lymphoma (8;14)
- activates expression of many genes involved in cell growth

Question 9

example of mutation that causes dysfunction of cell cycle regulators

Answer 9

(activating mutation of) cyclin/CDKs
- results in continuous proliferation of cells
- occurs in mantle lymphoma (11;14) of cyclin D1 gene

Question 10

how do cancer cells evade growth inhibitory signals (2)

Answer 10

1. inactivate tumour suppressor genes (recessive mutation)
2. inhibit mitogenic signalling pathways

Question 11

example of a recessive mutation that inactivates tumour suppressor genes

Answer 11

inactivation of retinoblastoma (negative regulator of cell cycle, prevents progression unless it’s phosphorylated by cyclin/CDK complex)
- loss of function mutation of RB genes
- gene amplification of cyclin D/CDK4 genes
- loss of CDK inhibitors
- viral oncoproteins that bind & inhibit RB

basically either inhibit RB or upregulate cyclin/CDK

Question 12

how do cancer cells evade apoptotic cell death

Answer 12

inhibit apoptotic factors or upregulate anti-apoptotic factors

Question 13

example of mutation of cancer cells that inhibit apoptotic factors

Answer 13

loss of p53 and hence its downstream effects (cell cycle arrest, DNA repair, apoptosis, inhibition of angiogenesis)

Question 14

example of mutation of cancer cells that upregulate anti-apoptotic factors

Answer 14

upregulation of BCL2
- occurs in follicular lymphoma
- translocation of BCL2 gene to promotor of IgH gene in lymphoid follicles (14;18)

Question 15

how do cancer cells have unlimited replicative potential

Answer 15

reactivates telomerase to maintain length of telomeres

Question 16

how do cancer cells induce angiogenesis for tumour survival & expansion

Answer 16

• mutation of proto-oncogenes to oncogenes that upregulate VEGF expression to stimulate angiogenesis
• loss of p53 in tumour cells that decrease antiangiogenic molecules, indirectly promoting angiogenesis

Question 17

7) how do cancer cells avoid immune destruction (2)

Answer 17

• secrete factors eg TGF-B that’s anti-inflammatory & hence immunosuppressing
• expression of PDL1 on DCs that bind to T cells and suppress T cell response

Question 18

8) what happens during reprogramming of energy metabolism by cancer cells

Answer 18

• cancer cells carry out glycolysis even in presence of O2 to allow diversion of glycolytic intermediates into various biosynthetic pathways
• increase glucose uptake & fermentation of glucose to lactate

Question 19

9) how does genome instability result in cancer (3)

Answer 19

1. cancer cells continue dividing despite DNA replication errors, passing mutation down
2. breakdown of DNA repair mechanism
3. breakdown of surveillance mechanism

Question 20

example of loss of function mutations that cause loss of MMR proteins (breakdown of DNA repair mechanism)

Answer 20

HNPCC⇒ loss of MMR proteins⇒ microsatellite instability (MS)⇒ microsatellites increase/decrease in length

Question 21

example of DNA methylation that causes inactivation of MMR gene

Answer 21

DNA methylation⇒ epigenic inactivation of MLH1 (an MMR gene)

Question 22

example of a mutation that results in the breakdown of surveillance mechanism

Answer 22

Li Fraumeni syndrome (germline mutation in p53 gene) resulting in 25fold increase in risk of developing cancer

Question 23

10) how does tumour promoting inflammation result in cancer

Answer 23

inflammation supplies growth factors, proangiogenic factors etc that contribute to multiple hallmark capabilities